title: Toxoplasma gondii Dense Granule Antigen 1 stimulates apoptosis of monocytes through autocrine TGF-β signaling.
abstract: Monocyte/macrophages represent the first line of defense against protozoan parasites. Different mechanisms of monocyte suppression by Toxoplasma gondii that sustain parasite invasion and persistence have been described, including apoptosis. In the present study, we investigated the effect of microbial excretory–secretory polypeptides, namely the microneme protein MIC3 and the dense granule antigen GRA1, on apoptosis of monocytes from patients with congenital toxoplasmosis and healthy individuals. We found that GRA1 but not MIC3 could induce apoptosis of monocytes, observing the effect in samples from both Toxoplasma-infected and uninfected individuals, thus ruling out involvement of mechanisms of apoptosis linked to adaptive immunity or a cellular context related to infection. Selective inhibition of TGF-β type I receptors reversed GRA1-induced apoptosis, indicating that this apoptosis involved canonical TGF-β signaling. By using TGF-β-neutralizing antibodies, we showed that monocyte apoptosis required endogenous TGF-β and that GRA1 stimulation activated TGF-β transcription and expression in monocytes but not lymphocytes, suggesting involvement of an autocrine TGF-β-mediated mechanism in GRA1-induced apoptosis.
authors.affiliation: Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: D'Angelillo
authors.forename: Elvira
authors.initials: E
authors.lastname: De Luna
authors.forename: Simona
authors.initials: S
authors.lastname: Romano
authors.forename: Rita
authors.initials: R
authors.lastname: Bisogni
authors.forename: Wilma
authors.initials: W
authors.lastname: Buffolano
authors.forename: Nicola
authors.initials: N
authors.lastname: Gargano
authors.forename: Paola
authors.initials: P
authors.lastname: Del Porto
authors.forename: Luigi
authors.initials: L
authors.lastname: Del Vecchio
authors.forename: Eskild
authors.initials: E
authors.lastname: Petersen
authors.forename: Maria Fiammetta
authors.initials: MF
authors.lastname: Romano
mesh_terms: D000328:Adult; D000953:Antigens, Protozoan / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002478:Cells, Cultured; D006801:Humans; D007223:Infant; D008297:Male; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism / Q000469:parasitology; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014122:Toxoplasma / Q000235:genetics / Q000378:metabolism*; D014123:Toxoplasmosis / Q000378:metabolism / Q000469:parasitology / Q000503:physiopathology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000953:Antigens, Protozoan; C412913:GRA1 antigen; C421382:MIC3 protein, Toxoplasma gondii; D015800:Protozoan Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1